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N-4 ( - ( ( 3- ( 2 -amino-4 pyrimidinyl) -2 -pyridinyl) oxy) phenyl) -4- (4-methyl-2-thienyl) -1-phthalazinamine for use in the treatment of antimitotic agent resistant cancer

A pyrimidinyl and pyridyl-based technology, applied in the fields of organic active ingredients, antineoplastic drugs, non-living medical raw materials, etc.

Inactive Publication Date: 2013-01-09
AMGEN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

More specifically, multidrug resistance is a problem
Additionally, such resistance to one or more anticancer treatments inevitably leads to patient death

Method used

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  • N-4 ( - ( ( 3- ( 2 -amino-4 pyrimidinyl) -2 -pyridinyl) oxy) phenyl) -4- (4-methyl-2-thienyl) -1-phthalazinamine for use in the treatment of antimitotic agent resistant cancer
  • N-4 ( - ( ( 3- ( 2 -amino-4 pyrimidinyl) -2 -pyridinyl) oxy) phenyl) -4- (4-methyl-2-thienyl) -1-phthalazinamine for use in the treatment of antimitotic agent resistant cancer
  • N-4 ( - ( ( 3- ( 2 -amino-4 pyrimidinyl) -2 -pyridinyl) oxy) phenyl) -4- (4-methyl-2-thienyl) -1-phthalazinamine for use in the treatment of antimitotic agent resistant cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Step 2: 4-(2-(4-Aminophenoxy)pyridin-3-yl)pyrimidin-2-amine

[0045] To a resealable tube was added 4-aminophenol (1.3 g, 12 mmol), cesium carbonate (7.8 g, 24 mmol) and DMSO (16 ml, 0.75 M). The mixture was heated to 100°C for 5 minutes, then 4-(2-chloropyridin-3-yl)pyrimidin-2-amine (2.5 g, 12 mmol) was added and the reaction mixture was heated to 130°C overnight. After completion (as identified by LCMS), the reaction mixture was cooled to RT and diluted with water. The resulting precipitate was filtered, and the solid was washed with water and diethyl ether. Then in 9:1 CH 2 Cl 2 : Dissolve solids in MeOH with 9:1 CH 2 Cl 2 :MeOH was passed through a pad of silica gel as eluent. The solvent was concentrated in vacuo to afford the desired product 4-(2-(4-aminophenoxy)pyridin-3-yl)pyrimidin-2-amine. MS m / z = 280 [M+1] + . C 15 h 13 N 5 O calculated value: 279.30.

[0046] Step 3: 1-Chloro-4-(4-methylthiophen-2-yl)phthalazine

[0047] 1,4-Dichloroph...

Embodiment 2

[0060] Washing and Fixing Solutions

[0061]

[0062] Reagent

[0063]

[0064] Laboratory equipment, supplies, software

[0065] Desktop refrigerated centrifuge Allegra X-15R centrifuge, Beckman Coulter, Fullerton, CA 92834 GraFit v5 software Erithacus Software, Horley Surrey, RH6 9YJ, UK XLfit 4.2 software Excel, Microsoft Inc., USA GraphPad Prism v5 GraphPad Software, Inc. 2236 Avenida de la Playa, La Jolla, CA 92037 Flow Cytometry Becton Dickinson LSRII flow cytometer, BD Biosciences, San Jose, CA 95131 96-well tissue culture plate, flat bottom low evaporation lid, sterile Cat. No. 3595, lot number not provided, Corning Incorp. Life Sciences, Lowell MA 01851 12-well tissue culture plate, flat bottom low evaporation lid, sterile Cat. No. 353043, Lot No. not provided, BD Labware, Franklin Lakes, NJ 07417 6-well tissue culture plate, flat bottom low evaporation lid, sterile Cat. No. 353046, Lot No. not provided...

Embodiment 3

[0113] (ND) Not determined, resistance (r) defined as ≥10-fold loss of potency (EC50 value) compared to taxane-sensitive tumor cell lines

[0114] The effect of AMG 900 was determined on the multidrug resistant cell line MES-SA Dx5 grown in vivo as tumor xenografts. Mice were orally administered AMG 900 at 15 mg / kg twice a day or 3.0 mg / kg twice a day for 2 consecutive days a week during the study period. Dosing was initiated when tumors were established (10 days after tumor implantation). AMG 900 treatment with both AMG 900 doses and regimens resulted in statistically significant tumor growth inhibition compared to vehicle control group (Figure 4; p < 0.0001, Dunnett's post hoc test). Comparable tumor growth inhibition was also surprisingly achieved with similar treatment regimens in 2 other resistance models (HCT15 and NCI-H460-taxol resistance[r]) (see Table 4).

[0115] Figure 4: AMG 900 inhibits the growth of established MES-SA Dx5 xenograft tumors

[0116]

[0117]...

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PUM

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Abstract

The present invention relates to methods of using the compound, N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-(4-methyl-2-thienyl)-1-phthalazinamine or a pharmaceutically acceptable salt thereof, to treat cancers, including solid tumors, which have become resistant to treatment with chemotherapeutic agents, including anti-mitotic agents such as taxanes, and / or other anti-cancer agents, including aurora kinase inhibiting agents. The invention also includes methods of treating cancers refractory to such treatments by administering a pharmaceutical composition, comprising the compound to a cancer subject.

Description

[0001] related application [0002] This application claims the benefit of US Provisional Application No. 61 / 241,527, filed September 11, 2009, the specification of which is hereby incorporated by reference in its entirety. field of invention [0003] The present invention relates to N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridyl)oxy)phenyl)-4-(4-methyl-2-thienyl)-1 - Use of phthalazinamines for the treatment of cancers, including solid tumors, which have become resistant to treatment with anti-mitotic and / or other chemotherapeutic agents. Background of the invention [0004] Cancer is one of the most widespread diseases affecting humans and is the leading cause of death worldwide. In the United States alone, cancer is the second leading cause of death after heart disease. Cancer is often characterized by dysregulation of normal cellular processes or unregulated cell proliferation. Cells that have transformed into cancer cells tend to proliferate in an uncontrolled and unreg...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/502A61P35/00A61P35/02
CPCA61K31/502A61P35/00A61P35/02A61K9/0053A61K35/02
Inventor M.佩顿R.肯达尔
Owner AMGEN INC
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